Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

Weinstock, Joel V.; Blum, Arthur M.; Metwali, Ahmed; Elliott, David E.; Bunnett, Nigel W.; Arsenescu, Razvan

doi:10.4049/jimmunol.171.7.3762

Cited by 63 publications

(62 citation statements)

References 46 publications

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“…Moreover, CGRP is produced by and activates migratory cells such as lymphocytes, granulocytes, and monocytes (12)(13)(14). Receptors for CGRP may be induced by intestinal inflammation, as is the substance P neurokinin 1 receptor in T cells and in intestinal epithelial cells (3,15). Although systemic use of the peptide receptor antagonist CGRP-37 was shown to decrease TxAinduced inflammation (16), that study could not discriminate between the contributions made by central and ileal CGRP receptors to disease genesis or resolution.…”

mentioning

confidence: 71%

Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis

Bhargava¹,

Clifton²,

Mhaske³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Enteritis caused by Clostridium difficile toxin (Tx) is a nosocomial disease of increasing clinical concern, but the local mediators of C. difficile TxA inflammation are unknown. The potent vasodilator calcitonin gene-related peptide mediates neurogenic inflammation via the calcitonin receptor-like receptor (CLR). Here we examined the ileum-specific effects of reducing CLR on TxA ileitis by local preinjection of double-stranded RNAs. Treatment with CLR dsRNA for 7 d decreased CLR immunoreactivity, whereas treatment with non-CLR dsRNA did not. Subsequent injection of TxA in the same location increased CLR in rats treated with non-CLR dsRNA but not in rats treated with CLR dsRNA, documenting that local injection of dsRNA is effective in preventing the increase in CLR immunoreactivity in response to local TxA. After non-CLR dsRNA pretreatment, TxA induced robust intestinal secretion, myeloperoxidase activity, and histopathologic indications of inflammation including epithelial damage, congestion, neutrophil infiltration, loss of mucin from goblet cells, and increase in mast cell numbers. After CLR dsRNA pretreatment, TxA-induced changes in intestinal secretion and histopathologic inflammation were improved, including normal mucin staining and fewer resident mast cells. Loss of CLR prevented TxA-mediated activation of NF-κB and concomitant increases in pERK1/2 and TNF-α mRNA. Locally produced CLR plays a proinflammatory role in TxA ileitis via MAPK signaling and TNF-α. The results reported here strongly suggest that a local injection of dsRNA targeting CLR could be an effective local therapeutic approach at the inflammation site in the treatment of a growing, clinically relevant hospital-acquired disease, C. difficile infection.

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confidence: 71%

Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis

Bhargava¹,

Clifton²,

Mhaske³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In the gastrointestinal tract, SP and its neurokinin-1 receptor (NK-1R) are expressed on several intestinal cell types, including colonocytes (3)(4)(5), and mediate multiple functions, such as motility (6), mucosal permeability (7), chloride secretion (8), and colonic epithelial cell proliferation (9). Studies indicate a major proinflammatory role for SP and the NK-1R in intestinal inflammation of different etiologies (7,(10)(11)(12). Pharmacological antagonism of NK-1R (7,11,12) or genetic deletion of this receptor results in reduced intestinal inflammation in the acute model of colitis induced by Clostridium difficile toxin A (13).…”

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confidence: 99%

Substance P mediates antiapoptotic responses in human colonocytes by Akt activation

Koon

Zhao

Zhan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

100

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We examined the hypothesis that substance P (SP) and the neurokinin-1 receptor (NK-1R), both in vitro and in vivo, promote mucosal healing during recovery from colitis by stimulating antiapoptotic pathways in human colonic epithelial cells. For the in vitro experiments, human nontransformed NCM460 colonocytes stably transfected with NK-1R (NCM460-NK-1R cells) were exposed to SP, and cell viability assays, TUNEL assays, and Western blot analyses were used to detect apoptotic and antiapoptotic pathways. SP exposure of NCM460-NK-1R colonocytes stimulated phosphorylation of the antiapoptotic molecule Akt and inhibited tamoxifeninduced cell death and apoptosis evaluated by the cell viability assay and poly(ADP-ribose) polymerase cleavage, respectively. SP-induced phosphorylation of Akt and cleavage of poly(ADPribose) polymerase were inhibited by blockade of integrin ␣V␤3, Jak2, and activation of phosphatidylinositol 3-kinase. For the in vivo experiments, C57BL/6 mice, administered 5% dextran sulfate (DSS) dissolved in tap water for 5 days followed by a 5-day recovery period, were treated with the NK-1R antagonist CJ-12,255 or vehicle. Vehicle-treated mice showed increased colonic Akt phosphorylation and apoptosis compared with mice that received no DSS. In contrast, daily i.p. administration of CJ-12,255 for 5 days post-DSS suppressed Akt activation, exacerbated colitis, and enhanced apoptosis, and pharmacologic inhibition of Akt, either alone or together with CJ-12,255, produced a similar effect. Thus, SP, through NK-1R, possesses antiapoptotic effects in the colonic mucosa by activating Akt, which prevents apoptosis and mediates tissue recovery during colitis.apoptosis ͉ colitis

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“…The IL-10-deficient mouse spontaneously develops intestinal inflammation that Department of Internal Medicine, Division of Gastroenterology-Hepatology, University of Iowa, Iowa City, IA 52242 worsens as the animal ages. NK-1R antagonists suppress intestinal IFN-␥ production and inhibit the ongoing colitis (20).…”

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confidence: 99%

Cutting Edge: Hemokinin Has Substance P-Like Function and Expression in Inflammation

Metwali

Blum

Elliott

et al. 2004

The Journal of Immunology

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Substance P (SP) belongs to the tachykinin family of molecules. SP, cleaved from preprotachykinin A, is a neuropeptide and a proinflammatory leukocyte product. SP engages neurokinin 1 receptor (NK-1R) to stimulate cells. Hemokinin (HK) is another tachykinin that binds NK-1R. HK comes from preprotachykinin C, which is distinct from preprotachykinin A. We determined whether HK functions like SP at inflammatory sites. Preprotachykinin C mRNA was in murine schistosome granulomas and intestinal lamina propria mononuclear cells. Granuloma T cells and macrophages expressed preprotachykinin C mRNA. HK bound granuloma T cell NK-1R with high affinity. SP and HK stimulated IFN-γ production with equal potency. NK-1R antagonist blocked the effect of SP and HK on IFN-γ secretion. Thus, both HK and SP are expressed at sites of chronic inflammation and share cell origin, receptor, and immunoregulatory function. Two distinct but functionally overlapping tachykinins govern inflammation through NK-1R at sites of chronic inflammation.

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Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

Cited by 63 publications

References 46 publications

Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis

Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis

Substance P mediates antiapoptotic responses in human colonocytes by Akt activation

Cutting Edge: Hemokinin Has Substance P-Like Function and Expression in Inflammation

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